# Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An In Silico and In Vitro Modeling Approach

## TL;DR

This study explores new nonpeptide compounds that may help treat high blood pressure with fewer side effects than current medications.

## Contribution

The study introduces isoindoline-1,3-diones as novel nonpeptide ACE inhibitors with promising in vitro and in silico results.

## Key findings

- Isoindoline-1,3-dione D-05 showed strong ACE inhibition with an IC50 of 416.4 μM.
- Isoindoline-1,3-diones exhibited lower toxicity in mice compared to isoindolines.
- The compounds effectively bind to the ACE catalytic active site in silico.

## Abstract

Hypertension, a major cardiovascular risk factor, is
often treated
with peptide-derived angiotensin-converting enzyme inhibitors (ACEi),
which can have several side effects. This study examined a new alternative:
isoindoline and isoindoline-1,3-dione derivatives as nonpeptide ACE
inhibitors. The synthesis and testing of these compounds involved
both in silico molecular docking studies and optimized in vitro inhibitory kinetic assays, along with acute toxicity
tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest
ACE inhibition in vitro (IC50 = 416.4
μM) and effectively bound to the enzyme’s catalytic active
site in silico. Additionally, isoindoline-1,3-diones
showed lower toxicity in mice (LD50 > 1600 mg/kg) compared
to isoindolines (LD50 < 1000 mg/kg). This reduced toxicity
is attributed to the presence of fewer reactive secondary metabolites.
These promising results highlight the potential of isoindoline-1,3-diones
as innovative nonpeptide ACE inhibitors and support further in vivo studies to verify their antihypertensive effects.